Compounds / FOXO4-DRI
FOXO4-DRI
Also known as: FOXO4 D-Retro-Inverso peptide; FOXO4-DRI; forkhead box O4 senolytic peptide
Primary research focus: Senolytic and aging research (selective clearance of senescent cells)
Last updated July 2026 · Reviewed against FDA labeling and published research.
What is FOXO4-DRI?
FOXO4-DRI is a synthetic senolytic peptide designed to selectively kill senescent ('zombie') cells. It is a D-retro-inverso peptide (built from D-amino acids in reversed order for protease resistance) derived from the FOXO4 forkhead domain and fused to a cell-penetrating sequence. It disrupts the FOXO4-p53 interaction that keeps senescent cells alive, triggering their apoptosis. It is a research compound with no FDA approval and no human clinical data.
In senescent cells, the transcription factor FOXO4 sequesters p53 in the nucleus, preventing p53 from initiating apoptosis and thereby keeping damaged senescent cells alive. FOXO4-DRI competitively binds the p53 transactivation domain (a 2025 NMR study characterized binding to p53 TAD2 with a Kd of roughly 400 nM), displacing p53 from FOXO4. Freed p53 relocates to the mitochondria and induces intrinsic apoptosis selectively in senescent cells, which depend on this axis, while sparing most healthy cells where FOXO4 is minimally expressed.
How it’s supplied
Not an FDA-approved or commercially available medicine. It is sold as a research-grade lyophilized peptide for reconstitution and laboratory use. Because it is a D-amino acid peptide, it is expensive to synthesize, and research-grade products are not FDA-reviewed for potency or sterility.
Dosage Chart
Units shown are for a U-100 insulin syringe (100 units = 1 mL), calculated from the vial size and BAC water you select. Always confirm against your prescription and your syringe markings.
| Phase | Dose | Frequency | Notes |
|---|---|---|---|
| Weeks 1-4 | 250mcg | 1x Daily | — |
| Weeks 5-8 | 375mcg | 1x Daily | — |
| Weeks 9-16 | 500mcg | 1x Daily | — |
- Rotate injection sites to reduce irritation and lipohypertrophy
- Not for use during pregnancy or breastfeeding
- Do not exceed the recommended dose to try to speed results
Potential Benefits and Side Effects
Effects reported in published research. Not a promise of results, and not medical advice.
- Reported in preclinical (mouse and cell) research only; human efficacy and safety are not established.
- Selective apoptosis (senolysis) of senescent cells while largely sparing healthy cells in models.
- Restored physical fitness, fur density, and renal function in naturally aged mice.
- Reduced chemotherapy-associated senescence and toxicity in mouse models.
- Proposed applicability to age-related tissue dysfunction and to therapy-induced senescence.
- No human adverse-effect data are available.
- Mouse studies reported no significant overt toxicity and generally improved health markers.
- Theoretical risks include off-target apoptosis given senescent-cell heterogeneity and impairment of the beneficial roles of senescence (wound healing, tumor suppression).
Warnings and contraindications
Important safety information. This is not exhaustive — read the full prescribing information and consult your prescriber or pharmacist.
- No FDA-approved labeling exists; the following reflect the compound's status and the limits of its evidence, not established label warnings.
- There are no human clinical trials or published human safety data for FOXO4-DRI.
- Modulating the p53 pathway warrants careful evaluation; senescent cells are heterogeneous, so selectivity may be incomplete and some healthy or quiescent cells could be affected.
- Senescent cells also play beneficial roles (for example in wound healing and tumor suppression), so excessive clearance could be harmful.
- Research-grade material varies in identity and purity.
- Safety in pregnancy and breastfeeding has not been studied.
- Not established; no FDA-approved labeling. Precautionary considerations include known hypersensitivity and any condition where interfering with senescence or p53 dynamics could be harmful.
Reconstitution Steps
How to prepare the lyophilized vial. Confirm specifics with your pharmacist or prescriber.
- Confirm the amount of peptide in the vial and the volume of diluent you intend to use before starting.
- Wash your hands and gather supplies: the lyophilized vial, the diluent (typically bacteriostatic water), an alcohol swab, and a sterile syringe.
- Let the vial and diluent reach room temperature if they were refrigerated or frozen.
- Wipe the rubber stopper of both the peptide vial and the diluent vial with a fresh alcohol swab and let them air dry.
- Draw the intended diluent volume into the syringe.
- Insert the needle into the vial and slowly release the diluent down the inside wall rather than directly onto the powder, to avoid foaming.
- Do not shake. Gently swirl or roll the vial until fully dissolved.
- Inspect the solution: it should be clear and colorless with no visible particles. Do not use if cloudy or containing particles.
- Note the resulting concentration (amount divided by diluent volume) so it matches the reconstitution calculator on this page.
- Label the vial with the reconstitution date and store as directed under reconstituted storage.
US regulatory status
Classifications are public record but can change. For reference only, not legal advice.
Development: FOXO4-DRI was introduced by Baar et al. (Cell, 2017), who showed that senescent cells depend on a FOXO4-p53 interaction and that a D-retro-inverso peptide disrupting it could selectively clear senescent cells, restoring fitness, fur density, and renal function in aged and chemotherapy-treated mice. Subsequent independent preclinical work extended the concept (for example, selective removal of senescent human chondrocytes in vitro), and a 2025 NMR study characterized the structural basis of p53 binding. More potent successor peptides (for example ES2) have since been reported. All evidence remains preclinical (cell and rodent); there are no registered or completed human clinical trials as of mid-2026, though analog development toward Phase 1 has been discussed.
Notes: FOXO4-DRI is not FDA-approved and has no recognized clinical use. It has no IND and is sold only as a research reagent, outside FDA quality oversight. It is not on the FDA 503A bulk drug substances list and is not eligible for 503A or 503B compounding. It is not a controlled substance.
International status
Pharmacokinetics
Storage and handling
Important Notes
Practical considerations for consistency and safety.
- FOXO4-DRI is preclinical only; there are no human trials or human safety data.
- Unlike broad senolytics such as dasatinib plus quercetin (which have reached human trials), FOXO4-DRI has not advanced beyond animal and cell studies.
- It modulates the p53 pathway; selectivity for senescent cells is high in models but not absolute.
- More potent successor peptides have been reported in the literature.
- Research-grade D-peptide material varies in purity and is costly to synthesize.
Lifestyle Factors
- Studied in intermittent dosing schedules in animal models (senolytics are often given in short courses rather than continuously).
- Human lifestyle interactions are unstudied.
References
Related compounds
Important disclaimer
This page is an educational reference, not medical advice, a diagnosis, or a treatment recommendation, and not a substitute for your prescriber or pharmacist. Approval and regulatory status varies by compound and can change. Always confirm against current prescribing information and consult a qualified healthcare professional before making any decision about a medication.